All publications mentioned throughout this application are fully incorporated herein by reference, including all references cited therein.
Otomycosis is a fungal external ear canal infection that is caused by dermatophytes, especially Aspergillus Niger (80% to 90% of cases) and Candida albicans (second most common cause) [Ologe,-F-E, Nwabuisi,-C (2002) West Afr J Med 21:34-36]. The infection may be either acute or sub-acute and is characterized by inflammation, pruritus, and scaling, superficial epithelial exfoliation, mass of debris containing hyphae, suppuration and pain, which results in severe discomfort for the patient.
Until now, treatment has relied on a few drugs available in the market, which may be summarized as follows. Clotrisone® (Taro Pharmaceutical, Israel) is a combination of clotrimazole and betamethasone, is not specific for the treatment of Aspergillus Niger, but has been shown to be reliably effective in treating mild to moderate candidiasis, whereas the period of treatment is over 8 weeks. Similarly, Agisten® (Agis Pharmaceuticals Ltd., Bnei Brak, Israel) is also not specific for treatment of Aspergillus niger; it is reliably effective in treating mild to moderate candidiasis, with a period of treatment of more than 8 weeks as well.
Another drug is Pitrex (is used to designate antifungal preparations comprising as active ingredient tolnafatate—Tolnaftate 1%) (Teva Israel Pharmaceutical Ltd., Petah Tiqva, Israel) which is effective in treating superficial dermatophyte infections including corporis, cruris, pedis but not aspergillus infection. Dex-Otic (Teva Israel Pharmaceutical Ltd., Petah Tikya, Israel) is not effective against Aspergillus Niger and other fungal infections, but is effective against bacterial infection.
In addition, there is oral and topical treatment with Terbinafine (Lamisil®—is used to designate torbinafine hydrochloride, Novartis, Basel, Switzerland) for the treatment of systemic and topical mycosis (e.g., infections due to corporis, cruris, pedis, Alternaria, Curvularia, or Candida) [Villars and Jones (1992) Br J Dermatol. 126(Suppl 39):61-9].
Tevacutan cream (is used to designate Teva's antifungal cream comprising clotrimazole 1%, dexamethasone acetate 0.044%, and neomycin sulfate 0.645%) and Tevaderm his used to designate Teva's antifungal cream comprising diflucortolone valerate 0.1%, and isoconazole nitrate 1%) (Teva Israel Pharmaceutical Ltd., Petah Tikva, Israel) are also used against fungal infection but not for Aspergillus and Candida. However, these products are contraindicated to patients who have a history of tuberculosis, herpes simplex, varicella, vaxinia, external and canal perforation.
Griseofulvin is an antifungal agent first isolated from a Penicillium spp. in 1939. It is used to treat dermatophyte infections, e.g. skin infections such as jock itch, athlete's foot, and ringworm, as well as fungal infections of the scalp, fingernails, and toenails. Griseofulvin is effective after oral ingestion and reaches the skin and hair. Griseofulvin inhibits fungal mitosis by disrupting the mitotic spindle through interaction with polymerised microtubules. The compound is insoluble in water. The inventors have found that the solubility of griseofulvin was higher in admixture with high molecular weight substances, such as herbal agents (e.g. tea tree oil), but not in admixtures with saccharides or alcohol.
The present invention relates to a formulation comprised of betamethasone, griseofulvin and tea tree oil. The combination of the active agents, betamethasone, griseofulvin and tea tree oil provides an advantage over the use of each of the agents alone and over the formulations currently available in the market in that it can be assumed from the presented results that the combined effect of betamethasone and griseofulvin is the result of the additive role of the two drugs. Furthermore, the tree tea oil serves as a vehicle for griseofulvin, while also providing increased solubility for griseofulvin. Moreover, tea tree oil is rarely used as a monotherapy, but is more effective with other antifungal agents (Basset et al, 1990).